There are many skin disorders associated with the excessive production of sebum, or the abnormal proliferation of keratinocytes, or both. Examples of skin disorders include acne vulgaris, seborrheic dermatitis (also referred to as seborrheic eczema), seborrheic adiposa (also referred to as seborrheic oleosa), seborrheic sicca, psoriasis, eczema, contact dermatitis, irritant dermatitis, ichthyosis and keratosis pilaris. Seborrheic dermatitis is characterized by moderate erythema, dry, moist, or greasy scaling, and yellow crusted patches on various skin areas of the body, including the mid-parts of the face, ears, supraorbital regions, umbilicus, genitalia, and especially the scalp. Seborrheic adiposa is described as oily secretion occurring especially about the nose and forehead. Seborrheic sicca is characterized as dry scaly seborrheic dermatitis. Psoriasis is characterized by scaly, erythematous plaques that may become confluent. Ichthyosis is a non-inflammatory scaling, hyperkeratotic disorder of skin. Keratosis pilaris, or multiple keratin plugs in skin follicles, produces a bumpy appearance to the skin. Hyperkeratosis is common in chronic contact, irritant and atopic (eczema) dermatitis.
Acne vulgaris, more commonly called acne, is a common skin disorder affecting a large number of people. Acne can result in physical damage such as scarring or disfigurement. Additionally, acne can cause adverse emotional effects to the individuals afflicted with the condition. Acne results when sebaceous follicles, located primarily on the face and trunk, become obstructed with sebum and epithelial cells. Sebum is produced by sebaceous glands in the follicles and epithelial cells are desquamated from the walls of the follicles. The sebum and the desquamated epithelial cells obstruct the sebaceous follicles. Obstruction of the follicles creates microcomedones which may evolve into comedones (non-inflammatory lesions, e.g., open and closed comedones, i.e., whiteheads and blackheads) or inflammatory lesions (e.g., inflammatory nodules, pustules and papules). A residing anaerobic bacterium, Propionibacterium acnes (P. acnes) proliferates in this environment of excessive sebum and follicular cells and may produce localized inflammation. Acne can be primary (idiopathic) or secondary (due, for example, to the application of cosmetics). Included in the definition of acne for the purposes of the present invention are cosmetically undesirable skin conditions commonly referred to as pimples, blemishes, skin imperfections, etc.
Acne is currently treated either topically or systemically (Leyden, 1997, New Engl. J. Med. 336(16):1156-1162). Treatment of acne involves controlling sebum production, reducing epithelial cell proliferation, or both. The primary etiologic factor in acne is now thought to be excessive sebum production. A treatment best able to modify this will be most efficacious. The present state of the art is such that treatment with systemic drugs is the only current way to control excessive sebum production. These drugs are prescribed as therapies only in severe cases of acne. Drugs known to be effective in controlling sebum overproduction include estrogens, antiandrogens such as cyproterone acetate, spironolactone, and the retinoid isotretinoin.
Estrogen treatments for reducing sebum production are usually prescribed as a combination estrogen-progestin contraceptive. A high dose of estrogen is maximally beneficial, increasing the well-known risks of oral contraceptive therapy. A therapeutic response is slow in onset, not appearing for two to four months. Prolonged treatment is necessary. There are also disadvantages to the use of spironolactone to reduce sebum production. Maximal benefits of spironolactone are also delayed, and continual treatment with the drug is necessary to maintain the improvement. Therapeutic results are only modest because spironolactone is only a weak anti-androgen.
Because sebaceous glands are androgen-dependent, systemic administration of anti-androgens, such as cyproterone acetate, is an effective treatment. However, the use of anti-androgens is limited to nonpregnant women because of potential feminizing effects on a male fetus and demasculinizing effects in adult males.
In severe recalcitrant cases of acne, oral administration of isotretinoin is effective in reducing sebum production, but the use of this compound is limited by cost, adverse side effects and teratogenicity.
Antibiotics, both systemic and topical, are used to decrease the proliferation of P. acnes, the bacterium responsible for the inflammatory lesions of acne. Systemic antibiotic treatments include tetracycline, erythromycin, minocycline, doxycycline, clindamycin, and trimethoprim-sulfamethoxazole. Topical antibiotic therapy for acne may include the administration of erythromycin, clindamycin, sulfacetamide, azelaic acid, benzoyl peroxide, or a combination of benzoyl peroxide and either erythromycin or glycolic acid. Although P. acnes is sensitive to many antibiotics in vitro, delivery of the antibiotics to the lipid-rich environment of the sebaceous follicles, in which the organism resides and proliferates, is difficult. Erythromycin is poorly lipophilic, clindamycin somewhat more so. Their efficacy is comparable. Benzoyl peroxide, although more lipophilic, also has its limitations. Although benzoyl peroxide is more effective in suppressing the growth of P. acnes than the topical formulations of clindamycin and erythromycin, benzoyl peroxide does not have any antinflammatory properties. Moreover, another disadvantage to using benzoyl peroxide in acne treatment is the local irritation and allergic contact dermatitis that may occur in the area of the skin being treated. Animal studies suggest that it may be carcinogenic. The disadvantage of using antibiotics as a treatment of acne is that most individuals require prolonged or frequent intermittent courses of antibiotic administration. Additionally, P. acnes is beginning to develop some antibiotic resistance, calling into question the future efficacy of antimicrobial therapy. It also contributes to the generalized development of antibiotic resistance in other pathogenic bacteria. Serious drug reactions have been associated with the use of clindamycin and sulfa drugs.
There has been little therapeutic progress since the introduction of retinoic acid and benzoyl peroxide two decades ago. Azelaic acid, just recently introduced, is not superior to any other topical therapies. Oral isotretinoin is highly effective but not widely available or applicable due to its significantly adverse side effect profile. The strict requirement for contraception is difficult to enforce, particularly in adolescents. There is clearly a need for an effective, safe and cosmetically palatable topical acne treatment.
The prior art describes no topical therapy for decreasing sebum production. Currently, excessive production of sebum is typically treated with facial cleansers, like soaps, detergents, and astringents, that work by merely removing sebum from the surface of the skin, rather than by reducing or inhibiting sebum production. The use of facial cleaners is actually counterproductive for a number of reasons. Cleansers and astringents emulsify necessary epidermal lipids and overly dry the skin. They paradoxically increase sebum production by causing hyperplasia of sebaceous glands and an increase in the cellular organelles responsible for sebum synthesis in sebocytes. Facial oiliness can be masked by "oil free" cosmetic preparations that contain clays, talcs, silicas, starches, polymers and other materials that temporarily absorb oil like a sponge. These formulations are limited by their sebum-absorbing capacity, formulation difficulties, negative aesthetic properties, and limited duration of effect. Women with acne may attempt to camouflage the symptoms by excessive application of makeup. Makeup is comedogenic and produces additional acne lesions.
Excessive follicular epithelial proliferation, keratinization and desquamation in sebaceous follicles leads to the formation of microcomedones. Known topical therapies for modifying the desquamation of follicular epithelial cells include the administration of retinoids such as tretinoin, isotretinoin and tazarotene, and the desquamating agent salicylic acid. Abnormal proliferation of keratinocytes produces follicular plugging, allowing sebum stasis and bacterial overgrowth. This results in increased bacterial hydrolysis of triglycerides to irritating free fatty acids and the inflammatory papulo-pustular lesions characteristic of acne.
Salicylic acid, therapeutically classified as a keratolytic agent, is extensively used as a desquamating agent. Salicylic acid exfoliates skin and leads to the extrusion of comedones, the primary lesion of acne. Unfortunately, salicylic acid is irritating and is limited to concentrations that are only partially efficacious. Salicylic acid has no effect on the production of sebum. Salicylic acid is not the preferred topical treatment; rather, benzoyl peroxide is more commonly used, suggesting that salicylic acid has only modest efficacy in the treatment of acne. In acne preparations, salicylic acid is used in concentrations of 0.5% to 2.0%. At a concentration of 0.5%, this compound is probably ineffective, at best minimally effective; however, the 0.5% concentration is marketed for the treatment of acne in individuals with sensitive skin. Salicylic acid at a concentration of 2.0% has modest efficacy. Efficacy potentially could be enhanced by increasing the concentration, however, such increased concentrations are contraindicated, since salicylic acid is extremely irritating because of its high acidity with a pH of 2.4. At a concentration of 17%, salicylic acid is commercially available to treat verruca vulgaris (warts) but carries a warning that this compound should not be applied to normal skin surrounding the lesion; irritated, infected or reddened skin; moles, birthmarks or hairy warts; or the face or mucuos membranes. Diabetics or individuals with circulatory problems are advised not to use it due to the risk of severe ulceration (Physicians' Desk Reference, Medical Economics Company, Montvale, N.J., p. 982 (1998). Salicyclic acid at a concentration of 5% is marketed to peel callouses and excessively cornified skin. It would not be appropriate for the tender and less cornified skin of the face. The prior art discloses methods to decrease its irritant properties by combination with pantothenic acid (U.S. Pat. No. 5,612,324) and ascorbic acid (U.S. Pat. No. 5,516,793). Its use in acne is reserved for mild cases primarily involving comedones and papules without a significant pustular or nodular component. This is also the case for benzoyl peroxide. Antibiotics and retinoic acid derivatives are more likely to be used in severe cases. The present invention further departs from the prior art by its applicability and therapeutic efficacy across the spectrum of disease severity.
Topical application of retinoic acid also decreases comedone formation. This compound may decrease follicular epithelial cell adhesion and may beneficially modulate cellular proliferation. Unfortunately, retinoic acid is very drying and irritating to the applied area. Furthermore, retinoic acid results in an increase in photosensitivity, making it necessary for the user to diligently avoid sun exposure.
The prior art describes the topical administration of derivatives of salicylic acid. U.S. Pat. No. 4,126,681 discloses compositions and methods for topical administration of an anti-inflammatory amount of acetylsalicylic acid to inflamed tissue. U.S. Pat. No. 4,665,063 discloses a composition and a method for the treatment of dermatological disorders by topically applying acetylsalicylic acid within a carrier. U.S. Pat. No. 4,933,330 discloses a composition and method for use in the treatment of psoriasis comprising 4-aminosalicylic acid or 5-aminosalicylic acid. The prior art employs these agents because they are anti-inflammatory; they do not address any of the other etiologic factors in acne. Incorporation of salicylate compounds into acne preparations has been suggested in order to improve the activity of the therapeutic ingredient. U.S. Pat. No. 5,019,567 discloses the use of quaternary ammonim lipophilic salicylate compounds to increase the stability of benzoyl peroxide and retard its decomposition. U.S. Pat. No. 4,299,826 discloses the use of a variety of penetration-enhancing agents for topical erythromycin compositions including benzyl and ethyl salicylate. U.S. Pat. No. 5,559,098 discloses the use of alkyl salicylate compounds to increase the lipophilicity of erythromycin in topical formulations.
Additionally, these compounds have drawbacks. Allergic reactions to acetylsalicylic acid are common, particularly in individuals with asthma, eczema and other allergic conditions. A disadvantage to using either 5-aminosalicylic acid or 4-aminosalicylic acid is that these compounds are chemically unstable on exposure to air and light, which results in shortened shelf life of the product. Furthermore, the U.S. Pharmacopia National Formulary, United States Pharmacopeial Convention, Inc., Rockville, Md., pp. 89-92 (1994) explicitly states that a prepared solution of 5-aminosalicylic acid or 4-aminosalicylic acid should not be used after 24 hours following preparation or if the product becomes discolored. Both are decarboxylated to the light-sensitive dye m-aminophenol. Since these compounds become easily discolored upon exposure to air and light, staining can occur of objects (e.g., clothes, linens, vanities) that contact either the compound or skin that has been treated with the compound. This is clearly pharmaceutically and cosmetically unacceptable. Moreover, it appears that the metabolism of 5-aminosalicylic acid to anionic salicylate does not occur in vivo; therefore, 5-aminosalicylic acid is not considered a true salicylate. (G. K. McEvoy, Ed., AHFS Drug Information, Section 56:40, p. 2434, American Society of Hospital Pharmacists, Inc., Bethesda, Md. (1998).)
There is a need for a method for treating and preventing excessive sebum production and abnormal keratinocyte proliferation with a topical agent, which is not keratolytic and caustic (thereby inhibiting the sebum production and abnormal keratinocyte proliferation) to inhibit skin disorders associated with these conditions. The present invention satisfies this need and overcomes the deficiencies of prior art treatments.
Salicylate salts and derivatives are extensively used in the oral form for the treatment of fever, pain and inflammation. This is based on their ability at therapeutic doses to inhibit prostaglandin synthesis. The prior art recognizes the use of topical salicylate containing compounds only as sunscreens (e.g., octyl salicylate) and anti-rheumatic agents (e.g., methyl salicylate).
The present invention is based on the discovery that anionic salicylate has the ability to prevent and treat acne and other skin disorders associated with the production of excessive sebum or abnormal proliferation of keratinocytes, without adversely affecting the skin at the dosage level necessary to reduce excessive sebum production or abnormal keratinocyte proliferation. The treatment may be prophylactic, palliative or curative.